QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.033928v1 71/6/1610    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Groner, E. Articles by Weinstock, M. Search for Related Content PubMed PubMed Citation Articles by Groner, E. Articles by Weinstock, M.

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

Department of Pharmacology, Hebrew University Medical Centre, Ein Kerem, Jerusalem, Israel (E.G., D.S-A., M.W.); Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel (Y.A.); and Teva Pharmaceutical Industries Ltd, Jerusalem, Israel (J.S., Y.H.)

Controlled inhibition of brain acetyl- and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of the OH-derivatives of rasagiline or selegiline that can serve as inhibitors of MAO-B and as antioxidants. We conducted a detailed in vitro kinetic study on two series of novel N-methyl, N-alkyl carbamates and compared them with rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k_i) and decarbamylation (k_r) of recombinant human AChE were mainly determined by the size of the N-alkyl substituent and to a lesser extent by the nature of the leaving group. k_i was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that k_i depends on a delicate balance between the length of the residue and its degree of freedom of rotation. By contrast, presumably because of its wider gorge, inhibition of human BChE was less influenced by the size of the alkyl group and more dependent on the structure of the leaving group. The data show how the degree of enzyme inhibition can be manipulated by structural changes in the N-methyl, N-alkyl carbamates and the corresponding leaving group to achieve therapeutic levels of brain AChE, BChE, and MAO-B inhibition.

Address correspondence to: Professor Marta Weinstock, Department of Pharmacology, Hebrew University, Ein Kerem, Jerusalem 91120, Israel. E-mail: martar{at}ekmd.huji.ac.il